Cuprizone‐induced demyelination triggers a CD8‐pronounced T cell recruitment

Abstract

The loss of myelinating oligodendrocytes is a key characteristic of many neurological diseases, including Multiple Sclerosis (MS). In progressive MS, where effective treatment options are limited, peripheral immune cells can be found at the site of demyelination and are suggested to play a functional role during disease progression. In this study, we hypothesize that metabolic oligodendrocyte injury, caused by feeding the copper chelator cuprizone, is a potent trigger for peripheral immune cell recruitment into the central nervous system (CNS). We used immunohistochemistry and flow cytometry to evaluate the composition, density, and activation status of infiltrating T lymphocytes in cuprizone‐intoxicated mice and post‐mortem progressive MS tissues. Our results demonstrate a predominance of CD8+ T cells along with high proliferation rates and cytotoxic granule expression, indicating an antigenic and pro‐inflammatory milieu in the CNS of cuprizone‐intoxicated mice. Numbers of recruited T cells and the composition of lymphocytic infiltrates in cuprizone‐intoxicated mice were found to be comparable to those found in progressive MS lesions. Finally, amelioration of the cuprizone‐induced pathology by treating mice with laquinimod significantly reduces the number of recruited T cells. Overall, this study provides strong evidence that toxic demyelination is a sufficient trigger for T cells to infiltrate the demyelinated CNS. Further investigation of the mode of action and functional consequence of T cell recruitment might offer promising new therapeutic approaches for progressive MS.

Interleukin-17 and Th17 Lymphocytes Directly Impair Motoneuron Survival of Wildtype and FUS-ALS Mutant Human iPSCs

“…Preliminary data suggest the presence of CD4+ and CD8+ T cells in the spinal cord and brain of ALS [ 19 ] and T cell subset alterations in the peripheral blood of ALS patients [ 20 , 21 , 22 ]. The presence of adaptive immune cells in the CNS of ALS patients is in line with the idea that a brain-intrinsic degenerative process can trigger the recruitment of peripheral immune cells [ 23 , 24 , 25 , 26 , 27 ]. Interestingly, recent studies provide evidence of the relevant role of T helper (Th)17 cells and their activation, both in animal models and patients with ALS [ 22 , 28 ].…”

What Guides Peripheral Immune Cells into the Central Nervous System?

“…In a recent study, we were able to show that, during the course of acute cuprizoneinduced demyelination, the recruitment of lymphocytes can be observed [76]. Interestingly, in contrast to most EAE models where inflammatory infiltrates are dominated by CD4 + T-cells [77], CD8 + cytotoxic T-cells outnumbered CD4 + T-helper cells.…”

Cuprizone Intoxication Results in Myelin Vacuole Formation

“…It is currently unclear, whether in MS such myelin abnormalities are induced by peripheral immune cells, can trigger or promote autoimmunity or promote the recruitment of peripheral immune cells. On the one hand, myelin vacuoles were found in the NAWM of MS patient material, where T cell densities are low (Kaddatz et al, 2021), suggesting that myelin disintegration might be an early event during MS lesion formation. On the other hand, similar abnormalities (i.e., myelinosomes) have been described in the autoimmune MS model EAE (Romanelli et al, 2016).…”

“…We and others recently demonstrated that metabolic oligodendrocyte stress, induced by intoxication with the mitochondrial toxin cuprizone, results in myelin basic protein (MBP) citrullination which triggers autoimmune inflammatory demyelination (Scheld et al, 2016;Caprariello et al, 2018;Kaddatz et al, 2021). The ultrastructure of the myelin-axonal unit in the cuprizone model has been described in early works, demonstrating swellings of the inner tongue of the myelin sheath similar to the observed myelin detachments in MS and the EAE model (Blakemore, 1973;Ludwin and Johnson, 1981).…”